US6107318A - Naphthothiazolone derivatives active on the D3 dopaminergic receptor - Google Patents

Naphthothiazolone derivatives active on the D3 dopaminergic receptor Download PDF

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US6107318A
US6107318A US09/424,858 US42485899A US6107318A US 6107318 A US6107318 A US 6107318A US 42485899 A US42485899 A US 42485899A US 6107318 A US6107318 A US 6107318A
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Felice Pocchiari
Claudio Masotto
Paolo Cavalleri
Stefania Montanari
Francesco Santangelo
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Zambon Group SpA
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Zambon Group SpA
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Assigned to ZAMBON GROUP S.P.A. reassignment ZAMBON GROUP S.P.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CAVALLERI, PAOLO, MASOTTO, CLAUDIO, MONTANARI, STEFANIA, POCCHIARI, FELICE, SANTANGELO, FRANCESCO
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/84—Naphthothiazoles

Definitions

  • the present invention relates to 4,5,6,7-tetrahydro-naphthothiazolone derivatives selectively active on the D 3 dopaminergic receptor.
  • the D 3 dopaminergic receptor was cloned for the first time by Sokoloff et al. (Nature. 347. 146. 1990), and is abundant in the cerebral areas connected to the emotional and cognitive functions.
  • the D 3 -antagonists are said to have a potential use as antipsychotics. e.g. in the therapy of schizophrenia, schizo-emotional diseases, psychotic depression, manias.
  • the pathologies which may be treated with the D 3 -receptor agonists include dyskinesia, such as Parkinson's disease, neuroleptic parkinsonism and late dyskinesia, and also depression, anxiety, memory failure, sexual disorders, drug addiction (e.g. from cocaine).
  • n is an integer comprised between 2 and 6.
  • R 1 is a methyl group or a group ##STR4## wherein R 2 , R 3 and R 4 are independently hydrogen, hydroxy, methoxy, methylsulfonyl, or one of R 2 , R 3 and R 4 together with another one of the three substituents forms a --O--CH 2 --O-- bridge;
  • the compounds of formula I have at least an asymmetric centre, marked by an asterisk, and may therefore be in form of stereoisomers.
  • Object of the present inventions are the compounds of formula I in form of stereoisomeric mixture and also as single stereoisomers.
  • the compounds of formula I are active on the D 3 dopamineraic receptors also by oral route. They are therapeutically useful in the treatment of psychotic diseases, such as schizophrenia, dyskinesia, such as Parkinson's disease, of depression, anxiety, memory diseases, sexual disorders and drug addiction.
  • psychotic diseases such as schizophrenia, dyskinesia, such as Parkinson's disease, of depression, anxiety, memory diseases, sexual disorders and drug addiction.
  • Preferred compounds of formula I are the ones wherein the carbon atom marked by an asterisk has the S configuration.
  • salts of the compounds of formula I are salts with organic and inorganic acids such as, e.g., hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, acetic, benzoic, maleic, fumaric, succinic, citric, aspartic, methansulfonic and 3,7-di-t.butylnaphthalen-1,5-disulfonic (dibudinic acid).
  • organic and inorganic acids such as, e.g., hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, acetic, benzoic, maleic, fumaric, succinic, citric, aspartic, methansulfonic and 3,7-di-t.butylnaphthalen-1,5-disulfonic (dibudinic acid).
  • the nitro group of the compound of formula IV is reduced to amino by hydrogenation in the presence of a catalyst made of a metal such as palladium, platinum, nickel, rhodium and ruthenium; in the meantime the polfluoroalkylsulfonyioxy group is reduced, thus obtaining a compound of formula V ##STR8## wherein PG is as defined above, which is reacted with a thiocyanate such as, for example, ammonium or alkali metal thiocyanate, in acidic environment to give a compound of formula VI ##STR9## wherein PG is as defined above.
  • This compound is cyclized to an aminothiazole derivative by heating in the presence of thionyl chloride or bromine in chloroform, and then turned in the equivalent diazonium salt applying known techniques.
  • the diazonium salt is turned in the compound of formula VII ##STR10## wherein PG is as defined above, by treatment with copper(I)chloride.
  • the compound of formula VII may be directly obtained from the aminothiazole compound by treatment with copper(II)chloride and t-butylnitrite.
  • the compound of formula IX is reacted under dehydrating conditions with an acid of formula X ##STR12## wherein n is as defined above and R 6 is hydrogen or a group ##STR13## wherein R 2 , R 3 and R 4 are as defined above, or with a reactive derivative thereof such as an acyl halide or a mixed anhydride which may also be prepared in situ in an inert solvent in the presence of a base such as an alkali carbonate or bicarbonate or a tertiary amine, to give an intermediate of formula XI ##STR14## wherein n and R 6 are as defined above, which is treated with hydrochloric acid in hot tetrahydrofiran and subsequently reduced on all the present amido groups by a reducing agrent such borane or borane complexes, for example, with methylsulfide or lithium aluminium hydride, to give the compounds of formula I.
  • a specific alternative relates to the compounds of formula I wherein n is 2 and R 1 is methyl which may be prepared by reacting the compound offormula VIII above with a double amount of propionic aldehyde under the just mentioned conditions.
  • a compound of formula IX is thus obtained ##STR15## wherein R 5 is hydrogen or a propyl group.
  • the compounds of formula I in optically active form are obtained by optical separation or through stereospecific or stereoselective synthesis.
  • the compounds of formula I are active on the D 3 dopaminergic receptors.
  • the interaction test with other receptorial systems showed that the compounds of formula I do not notably interact and thus they are endowed with high specificity (Example 12).
  • these compounds may be used as selective markers for the D 3 receptors optionally in form of radioligands.
  • the compounds of formula I may be administered both parenterally and enterally.
  • the therapeutical doses usually range between 0.1 mg and 400 mg a day by oral route for single administration.
  • Another object of the present invention are the pharmaceutical compositions containing a therapeutically effective amount of the compounds of formula I or the pharmaceutically acceptable salts thereof in admixture with a suitable carrier.
  • compositions of the invention may be liquid, suitable to the enteral or parenteral administration, and, preferably, solid such as tablets, capsules, granulates, suitable to the oral administration.
  • compositions of the invention may be carried out according to common techniques.
  • a further object of the invention relates to diagnostic kit containing one of the compounds of formula I optionally in form of radioligand.
  • the chromatographic purifications were effected on silica gel columns (230-400 mesh). Unless otherwise specified, the mass spectra were effected under the following conditions: chemical ionisation, isobutane, positive ions.
  • the organic phase was washed first with a 1N solution of HCl (200 ml) then with water (200 ml), anhydrified over Na 2 SO 4 and the solvent evaporated under reduced pressure.
  • the crude was dissolved in acetonitrile (300 ml)
  • the resulting solution wvas added with K 2 CO 3 (12.5 g; 90.7 mmoles) and, dropwise, with a solution of N-phenyltrifluoromethansulfonimide (17 g; 47.6 mmoles) in acetonitrile (100 ml) at room temperature.
  • the mixture was stirred at room temperature for 18 hours, then the solvent was evaporated under reduced pressure.
  • the product was subsequently turned into the corresponding hydrochloride by dissolution into ethyl acetate saturated with HCl followed by evaporation of the solvent under reduced pressure.
  • the organic phase was washed first with a 5% solution of KHCO 3 then with water, anhydrified over anhydrous Na 2 SO 4 and concentrated to dryness under reduced pressure, the residue was dissolved in THF (15 ml) and the solution was added with 3 drops of 37% HCl.
  • the reaction mixture was heated to 60° C. for 6 hours, then evaporated to dryness under reduced pressure and the resulting residue was added with methylene chloride and water.
  • the phases were separated and the organic one was washed with water, anhydrified over anhydrous Na 2 SO 4 and concentrated to dryness under reduced pressure.
  • CHO Chinese hamster ovary cells
  • NM9D murine mesencephalic neuronal
  • the cell lines were grown on Petri dishes, in a mixture of DMEM and Ham's F12 medium 1:1 supplemented with 10% foetal bovine serum (FBS), penicillin, streptomycin, geneticin (500 ⁇ g/ml) and glutamin in a humidified 5% CO 2 atmosphere at 37° C.
  • the membrane solution was aliquotated in portions of from 1 to 1.5 ml at a protein concentration of about 3 mg/ml (measures by a Bio-Rad protein assay based on the differential change of colour of a dye in response to different concentration of protein), placed in plastic tubes, rapidly frozen in liquid nitrogen and stored at -80° C.
  • the binding test was performed as reported by Billard et al. 1984, Life Sciences, 35. 1885-1893. Seabrook et al. 1992, FEBS, 312, 123-126 and Sunahara et al. 1991, Nature, 350, 614-619.
  • the compounds of formula I show to selectively bind D 3 receptor having an affinity constant for the remaining tested receptors neatly higher.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US09/424,858 1997-06-13 1998-06-12 Naphthothiazolone derivatives active on the D3 dopaminergic receptor Expired - Fee Related US6107318A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ITMI97A1398 1997-06-13
IT97MI001398A IT1292155B1 (it) 1997-06-13 1997-06-13 Derivati naftotiazolonici attivi sul recettore dopaminergico d 3
PCT/EP1998/003560 WO1998056778A1 (en) 1997-06-13 1998-06-12 Naphthothiazolone derivatives active on the d3 dopaminergic receptor

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US6107318A true US6107318A (en) 2000-08-22

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EP (1) EP0988296B1 (enrdf_load_html_response)
AT (1) ATE230735T1 (enrdf_load_html_response)
DE (1) DE69810622T2 (enrdf_load_html_response)
ES (1) ES2189211T3 (enrdf_load_html_response)
IT (1) IT1292155B1 (enrdf_load_html_response)
WO (1) WO1998056778A1 (enrdf_load_html_response)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050197385A1 (en) * 2004-02-20 2005-09-08 Schwarz Pharma Ag Use of rotigotine for treatment or prevention of dopaminergic neuron loss
US20070072917A1 (en) * 2003-07-26 2007-03-29 Srz Properties, Inc. Substituted 2-aminotetralin for the treatment of depression
US20070093546A1 (en) * 2003-07-26 2007-04-26 Srz Properties, Inc. Use of rotigotine for the treatment of depression
US20070191470A1 (en) * 2004-03-24 2007-08-16 Dieter Scheller Use of rotigotine for treating and preventing parkinson's plus syndrome
US7309497B2 (en) 2000-08-24 2007-12-18 Schwarz Pharma Ag Injectable pharmaceutical composition for systematic administration of pharmacologically active ingredients
US20080146622A1 (en) * 2003-12-24 2008-06-19 Srz Properties, Inc. Use Of Substituted 2-Aminotetralins For Preventive Treatment Of Parkinson's Disease

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10359528A1 (de) 2003-12-18 2005-07-28 Schwarz Pharma Ag (S)-2-N-Propylamino-5-hydroxytetralin als D3-agonistisches Therapeutikum

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994021608A1 (en) * 1993-03-25 1994-09-29 The Upjohn Company Indoletetralins having dopaminergic activity
US5639770A (en) * 1992-05-29 1997-06-17 Otsuka Pharmaceutical Co., Ltd. Thiazole derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5639770A (en) * 1992-05-29 1997-06-17 Otsuka Pharmaceutical Co., Ltd. Thiazole derivatives
WO1994021608A1 (en) * 1993-03-25 1994-09-29 The Upjohn Company Indoletetralins having dopaminergic activity

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7309497B2 (en) 2000-08-24 2007-12-18 Schwarz Pharma Ag Injectable pharmaceutical composition for systematic administration of pharmacologically active ingredients
US20070072917A1 (en) * 2003-07-26 2007-03-29 Srz Properties, Inc. Substituted 2-aminotetralin for the treatment of depression
US20070093546A1 (en) * 2003-07-26 2007-04-26 Srz Properties, Inc. Use of rotigotine for the treatment of depression
US8754119B2 (en) 2003-07-26 2014-06-17 Ucb Pharma Gmbh Use of rotigotine for the treatment of depression
US20080146622A1 (en) * 2003-12-24 2008-06-19 Srz Properties, Inc. Use Of Substituted 2-Aminotetralins For Preventive Treatment Of Parkinson's Disease
US8283376B2 (en) 2003-12-24 2012-10-09 Ucb Pharma Gmbh Use of substituted 2-aminotetralins for preventive treatment of parkinson's disease
US20050197385A1 (en) * 2004-02-20 2005-09-08 Schwarz Pharma Ag Use of rotigotine for treatment or prevention of dopaminergic neuron loss
US20070191470A1 (en) * 2004-03-24 2007-08-16 Dieter Scheller Use of rotigotine for treating and preventing parkinson's plus syndrome
US7872041B2 (en) 2004-03-24 2011-01-18 Ucb Pharma Gmbh Use of rotigotine for treating and preventing Parkinson's plus syndrome

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ITMI971398A0 (enrdf_load_html_response) 1997-06-13
ES2189211T3 (es) 2003-07-01
DE69810622T2 (de) 2003-10-30
IT1292155B1 (it) 1999-01-25
ATE230735T1 (de) 2003-01-15
ITMI971398A1 (it) 1998-12-13
WO1998056778A1 (en) 1998-12-17
EP0988296A1 (en) 2000-03-29
EP0988296B1 (en) 2003-01-08
DE69810622D1 (de) 2003-02-13

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